CXCL12 and CXCR4 as Potential Early Biomarkers for Luminal A and Luminal B Subtypes of Breast Cancer

Figures & data

Table 1 Descriptive Analysis of Study Participants

Group of Patients	Breast Cancer Group	Luminal A Breast Cancer Subgroup	Luminal B Breast Cancer Subgroup	Fibroadenoma Group	Healthy Women Group
Median age (years)	59,5	60	59	48	52,5
	No. of cases	No. of cases	No. of cases	No. of cases	No. of cases
Age intervals
≤50 years	28	14	14	24	18
50-70 years	53	28	25	24	29
≥70 years	19	8	11	2	3
Menopause
Premenopause	–	–	–	–	–
Postmenopause	100	50	50	50	50
Histological type
Fibroadenoma	–	–	–	50	NA
Ductal carcinoma in situ	5	3	2	–	NA
Invasive Carcinoma of no special type	78	38	40	–	NA
Lobular carcinoma	12	5	7	–	NA
Mucinous adenocarcinoma	5	4	1	–	NA
Receptor status
ER, PR+; HER2-;  ki67<14%	50	50	–	NA	NA
ER, PR+; HER2-;  ki67≥14%	44	–	44	NA	NA
ER, PR+; HER2+;  ki67 – any value	6	–	6	NA	NA
Tumor stage
Stage Ia-Ib	68	36	32	NA	NA
Stage IIa	32	14	18	NA	NA

Abbreviations: ER, estrogen receptor; NA, not applicable; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2.

Figure 1 Analysis of CXCL12 mRNA expression levels in BC tissues. (A) Comparison of CXCL12 mRNA expression between BC and healthy tissue. (B) Comparison of CXCL12 mRNA expression between different BC subtypes. (C) Comparison of CXCL12 mRNA expression between different stages of BC.

Figure 2 Analysis of CXCR4 mRNA expression levels in BC tissues. (A) Comparison of CXCR4 mRNA expression between BC and healthy tissue. (B) Comparison of CXCR4 mRNA expression between different BC subtypes. (C) Comparison of CXCR4 mRNA expression between different stages of BC.

Table 2 Concentrations of CXCL12, CXCR4 and CA 15-3 in Individual Study Groups (Median Concentrations and Interquartile Ranges (IQR))

	CXCL12 [ng/mL]	CXCR4 [pg/mL]	CA15-3 [IU/mL]
BC group
MEDIAN	2.433	1525.32	20.95
IQR	2.157–2.690	432.63–3059.10	14.08–26.93
Luminal A BC subgroup
MEDIAN	2.479	1676.04	21.86
IQR	2.307–2.710	732.17–2948.01	13.60–27.70
Luminal B BC subgroup
MEDIAN	2.323	1343.65	20.27
IQR	1.963–2.676	768.25–3859.41	14.43–26.50
Fibroadenoma group
MEDIAN	2.503	1017.64	17.55
IQR	1.463–3.171	432.63–2386.01	10.97–24.72
Healthy women group
MEDIAN	2.920	1149.23	16.65
IQR	2.804–3.171	931.45–1310.34	10.54–21.48

Figure 3 CXCL12 concentrations in the study groups (including luminal A and B subgroups of BC) and control groups (fibroadenoma and healthy women). On the graphs were plotted the values of the median, interquartile range and the minimum and maximum values. Clusters indicate statistically significant differences between particular groups.

Figure 4 CXCR4 concentrations in the study groups (including luminal A and B subgroups of BC) and control groups (fibroadenoma and healthy women). On the graphs were plotted the values of the median, interquartile range and the minimum and maximum values. Clusters indicate statistically significant differences between particular groups.

Figure 5 CA 15-3 concentrations in the study groups (including luminal A and B subgroups of BC) and control groups (fibroadenoma and healthy women). On the graphs were plotted the values of the median, interquartile range and the minimum and maximum values. Clusters indicate statistically significant differences between particular groups.

Figure 6 Heatmaps of correlation matrix for tested groups: (A) – BC total group of patients, (B) – luminal A subgroup (LumA) of patients, (C) – luminal B subgroup (LumB) of patients, (D) – women with fibroadenoma (FA), (E) – healthy women (HW).

Table 3 Diagnostic Reliability of Univariate and Multivariate Parameters in the Respective Study Groups

Parameter	Diagnostic Reliability
	Sensitivity [%]	Specificity [%]	Positive Predictive Value [%]	Negative Predictive Value [%]	Accuracy [%]
Breast cancer group
CXCL12	79.00	82.00	89.77	66.13	80.00
CXCR4	55.00	80.00	85.32	47.06	63.33
CA 15-3	58.00	72.00	80.56	46.15	62.67
CXCL12 + CA 15-3	92.00	58.00	81.42	78.38	80.67
CXCR4 + CA 15-3	81.00	58.00	79.41	60.42	73.33
CXCL12 + CXCR4 + CA 15-3	96.00	48.00	78.69	85.71	80.00
Luminal A breast cancer subgroup
CXCL12	78.00	82.00	81.25	78.85	80.00
CXCR4	58.00	80.00	74.36	65.57	69.00
CA 15-3	60.00	72.00	68.18	64.29	66.00
CXCL12 + CA 15-3	92.00	58.00	68.66	87.88	75.00
CXCR4 + CA 15-3	82.00	58.00	66.13	76.32	70.00
CXCL12 + CXCR4 + CA 15-3	98.00	48.00	65.33	96.00	73.00
Luminal B breast cancer subgroup
CXCL12	80.00	82.00	81.63	80.39	81.00
CXCR4	52.00	80.00	72.22	62.50	66.00
CA 15-3	65.00	72.00	66.67	62.07	64.00
CXCL12 + CA 15-3	92.00	58.00	68.66	87.88	75.00
CXCR4 + CA 15-3	80.00	58.00	65.57	74.36	69.00
CXCL12 + CXCR4 + CA 15-3	94.00	48.00	64.38	88.89	71.00

Table 4 ROC Curves Characteristics for Univariate and Multivariate Parameters in the Respective Study Groups with the Assessment of the Quality of the Test Against the Comparative Marker CA 15-3

Parameter	AUC	SE (AUC)	95% C.I.	p (AUC=0.5)	pCA 15-3 (AUCCA 15-3)
Breast cancer group
CXCL12	0.8196	0.0367	0.7476–0.8916	<0.001	0.003
CXCR4	0.6054	0.0456	0.5161–0.6947	0.036	0.838
CA 15-3	0.6434	0.0460	0.5533–0.7335	0.004	–
CXCL12 + CA 15-3	0.8292	0.0343	0.7620–0.8964	<0.001	<0.001
CXCR4 + CA 15-3	0.7184	0.0405	0.6390–0.7978	<0.001	0.025
CXCL12 + CXCR4 + CA 15-3	0.8812	0.0274	0.8275–0.9349	<0.001	<0.001
Luminal A breast cancer subgroup
CXCL12	0.7952	0.0482	0.7008–0.8896	<0.001	0.039
CXCR4	0.6184	0.0641	0.4928–0.7440	0.041	0.972
CA 15-3	0.6422	0.0564	0.5316–0.7528	0.014	–
CXCL12 + CA 15-3	0.8184	0.0438	0.7326–0.9042	<0.001	<0.001
CXCR4 + CA 15-3	0.7196	0.0538	0.6141–0.8251	<0.001	0.119
CXCL12 + CXCR4 + CA 15-3	0.8736	0.0357	0.8037–0.9435	<0.001	<0.001
Luminal B breast cancer subgroup
CXCL12	0.8440	0.0412	0.7633–0.9247	<0.001	0.005
CXCR4	0.5924	0.0623	0.4697–0.7151	0.111	0.781
CA 15-3	0.6446	0.0551	0.5366–0.7526	0.013	–
CXCL12 + CA 15-3	0.8400	0.0406	0.7604–0.9196	<0.001	<0.001
CXCR4 + CA 15-3	0.7136	0.0527	0.6104–0.8168	<0.001	0.107
CXCL12 + CXCR4 + CA 15-3	0.9048	0.0301	0.8459–0.9637	<0.001	<0.001

Note: Values of p<0.05 are indicated in red.

Figure 7 ROC curves of univariate and multivariate parameters in a group of BC patients.

Figure 8 ROC curves of univariate and multivariate parameters in a group of in a luminal A BC subgroup of patients.

Figure 9 ROC curves of univariate and multivariate parameters in a group of in a luminal B BC subgroup of patients.